Specifically, it is a request to add a third Specific Aim, "To study lineage stability and directionality of hematopoiesis", to an ongoing project, AI-20069, entitled "Early Events in Mammalian B-Cell Differentiation". The experiments will rigorously test a new concept, i.e. that primitive hematopoietic cells can reverse differentiation and re-acquire some stem cell properties. Indeed, stem cells may normally oscillate between states before giving rise to lineage restricted progenitors. The same phenomenon could account for the ability of malignancies to retain rare tumor stem cells. A better understanding of the stability of blood forming cells will be informative about how the immune system is replaced in normal and disease circumstances. Given the innovative nature of the concept, the experiments may open an entirely new line of investigation. However, we need additional personnel and supplies, as well as bioinformatics and microarray support that can be obtained by affiliation with OMRF's NCRR supported COBRE, entitled "Science in a Culture of Mentoring (RR015577)". This COBRE has a proud record in mentoring and networking, as well as superb Core Facilities. Thus, the outstanding young investigator to be covered by this supplement will benefit from interactions with this COBRE and be groomed for eventual status as an independent faculty member. In addition, the PI of the parent RO1 will contribute expertise and mentoring to other participants in the COBRE. Animal models, normal human specimens and protocols are all ready to be used immediately, and the research plan can be completed in two years. PUBLIC HEALTH REVELANCE: Cells in the immune system are constantly replaced from rare stem cells that reside within bones. It has always been believed that this occurs in one direction, from stem cell to blood cell. However, exciting new findings suggest there is a degree of back and forth. More study could suggest new therapies for autoimmune, malignant and other diseases involving the immune system.